Dysregulation of the immune system underlies many autoimmune and inflammatory diseases. While genetic contributions to multiple sclerosis, type 1 diabetes and inflammatory bowel disease (IBD) are being studied, abundant new research highlights the importance of environmental factors. The gut microbiome, a consortium of microbes that colonize the human gastrointestinal tract, has emerged as a critical contributor to disease. Gut bacteria regulate the development and function of the immune system, and have been strongly implicated in IBD and experimental colitis. Recent seminal studies have identified that specific gut bacteria can suppress intestinal inflammation in preclinical models. Thus, development of probiotic therapies for IBD is a promising area of research. Our laboratory has described a leading model system for studying beneficial host-bacterial symbiosis. Bacteroides fragilis, a common member of the human microbiome, ameliorates gut inflammation and treats experimental colitis. We reveal striking new data that B. fragilis directly activates the autophagy pathway, and requires autophagy for its therapeutic activity. Autophagy is a cellular process whereby particles (such as pathogenic bacteria) are degraded and destroyed. Importantly, polymorphisms in autophagy genes are highly linked to human IBD. Our research uncovers a new role for autophagy, as a signaling pathway that is used by beneficial bacteria to mediate protection from colitis. This connection between the gut microbiome and autophagy has not been previously studied, and may have profound implications to the underlying cause(s) of IBD. This project will investigate novel mechanisms by which environmental (microbiome) and genetic (autophagy) factors merge to impact intestinal disease. We will test the innovative hypothesis that genetic defects in autophagy lead to IBD by preventing responses to protective signals from gut bacteria. Specific aims include: 1) defining the signaling pathways by which B. fragilis activates autophagy; 2) understanding how autophagy suppresses intestinal inflammation in preclinical models; 3) examining cells from IBD patients with polymorphisms in autophagy genes to elucidate how B. fragilis impacts human immune responses. These studies promise to uncover novel and fascinating interactions between gut bacteria and the immune system, by revealing a previously unappreciated link between the microbiome and autophagy. Upon completion, discoveries from this project will significantly advance our long-term goal of developing a safe and effective treatment for IBD.